Vaccination as a prophylactic measure to prevent infectious diseases has proven to be extremely successful, leading to the eradication of a few and keeping many infectious diseases under control. Despite success in systemic vaccination, there has been an increasing unmet demand for effective mucosal vaccination.
The mucosal surfaces in humans (ca. 400 m2 surface area) and animals are the major portals of entry and/or sites of diseases caused by bacterial, viral and parasitic pathogens. Examples of these diseases include those caused by enteropathogenic E. coli, H. pylori, Campylobacter spp., Salmonella spp, Vibrio cholerae, Shigella spp, rotaviruses, and calciviruses in the gastrointestinal (GI) tract; influenza virus, Mycobacterium tuberculosis, Mycoplasma pneumoniae, and respiratory syncytial virus in the respiratory tract; sexually transmitted diseases such as HIV, Neisseria spp., Chlamydia spp., and herpes simplex virus in the urogenital tract. However, the majority of currently licensed human and veterinary vaccines are administered parenterally and display only limited ability to elicit protective mucosal immunity. For example, systemic immunization with inactivated poliovirus can prevent development of poliomyelitis, but it fails to prevent infection in the GI tract or in the tonsils. Development of safe vaccines that elicit strong and prolonged mucosal immunity that would circumvent the attachment/colonization of pathogens to the mucosal epithelium, impede pathogen replication/penetration in the mucosa, and/or block activity of microbial toxins, would be a significant advancement in the prevention and treatment of a wide spectrum of infectious diseases. Mucosal vaccines would also improve patient compliance as well as alleviate safety and adverse reaction issues associated with injectable vaccines.
The mammalian mucosal immune system comprises innate, non-specific defenses and the adaptive immunologic network. Secretory IgA (S-IgA) is the best defined humoral effector component of the mucosal immune system, but its production is not sufficiently stimulated by current parenteral vaccines. The few mucosal vaccines currently on the market all use live-attenuated or dead whole cells. However, there are no mucosal vaccines using more defined protective antigens. Vaccines using subunit antigens are preferred from safety and regulatory perspectives. However, since most subunit antigens have poor immunogenicity and do not induce effective mucosal immunity on their own, potent mucosal adjuvants are required for the development of effective mucosal vaccines. Among the currently tested mucosal adjuvants, cholera toxin (CT) of V. cholerae and heat labile toxin (LT) of E. coli are the most effective. However, efforts to reduce the toxicity of these toxin adjuvants have generally also resulted in the loss or reduction of their mucosal adjuvanticity. The drawbacks of the current approaches to developing mucosal vaccines are fueling intense global efforts to develop novel, safe vaccines/adjuvants that can induce protective mucosal immunity in vaccinated hosts.
As noted above, there are regulatory concerns with the use of poorly defined whole cell vaccines, as well as with live-attenuated vaccines, and with bacterial or viral vectors. The potential reversion to virulence of live-attenuated vaccines, potential dominant immune response to the live vector instead of the desired antigen with use of viral/bacterial vectors, and the contradiction of giving such vaccines to increasingly immunocompromised populations in the world are mitigating factors against the use/approval of similar new vaccines. Therefore, new mucosal vaccines must investigate other strategies. Research approaches for non-replicating mucosal delivery vehicles and adjuvants have included virosomes, liposomes, cochleates, archaeal lipid mucosal adjuvant vaccine and delivery system (AMVAD), polymeric microspheres, mucoadhesive polymers, immune stimulating complexes (ISCOMS), and CpG DNA as delivery/adjuvant systems, and the use of potent mucosal adjuvants such as cholera toxin (CT) and heat labile toxin (LT) from E. coli. However, CT and LT holotoxins have unacceptable adverse effects in humans, while their detoxified derivatives demonstrate diminished adjuvanticities. Although CpG shows some promise, there are still concerns regarding DNA integration, duration of immunity and the eliciting of unfavourable immune responses. As a result, no non-replicating, defined subunit mucosal vaccine has been approved to date. The poor immune responses of non-replicating antigen vaccines given mucosally are at least partially due to the lack of transport of the antigen through the epithelial layer to the mucosal immune network and the effective activation of antigen-presenting cells.